"In another part of Chicago stood the institute for Nuclear
Research, in which men may have had theories upon the essential
worth of human nature but were half ashamed of them, since
no quantitative instrument had yet been designed to measure it."
-Isaac Asimov, "Pebble in the sky", 1958.

2.4.1 Neurotransmitters

All along the surface of the dendrites are contact points, the synapses. This
is were information is transmitted from one neuron to the next. In the
presynaptic terminals there are small spheres, the synaptic vesicles, which
contain a chemical substance that can be released into the synaptic cleft as a
response to electrical activity in the axon. The chemical that is released is
called a synaptic transmitter, or a neurotransmitter. This neurotransmitter
flows across the cleft and produces electrical changes in the postsynaptic
membrane (Rosenzweig et al., pp. 30-31, 1999).

There are six criteria for classifying a
molecule as a neurotransmitter: (From Rosenzweig et al., 1999, p. 82)

1. The chemical exists in the presynaptic terminal.
2. The enzymes for synthesising the
transmitter exist in the presynaptic terminals or, in the case of the peptides,
in the cell body.
3. The transmitter is released when nerve impulses reach the terminals, and in
sufficient quantities to produce normal changes in postsynaptic potentials.
4. Specific receptors exist on the postsynaptic membrane for the released
transmitter.
5. Experimental application of appropriate amounts of the chemical at the
synapse produces changes in postsynaptic potentials.
6. Blocking release of the substance prevents presynaptic nerve impulses from
altering the activity of the postsynaptic cell.

Some neurotransmitters and families of transmitters(this is table 4.1 in Rosenzweig et al.,
1999, p. 82).

- immunocytochemistry -- a procedure for locating particular proteins in the
brain by labelling antibodies to the neuroproteins with a dye or radioactive
element and then exposing the slices of brain tissue tot the labelled
antibodies.

- in situ hybridisation -- a technique for locating the mRNA of particular
proteins in the brain. Hybrid molecules that bind to the mRNA that directs the
synthesis of the target protein are synthesised; then these hybrid ligand are
labelled, and brain slices exposed to them.

- autoradiography -- the technique of photographically developing brain
slices that have been exposed to a radioactively labelled substance such as
2-deoxyglucose so that regions of high uptake are visible on the brain slices.

2.4.1.1 Acetylcholine (ACh)

Acetylcholine was the first neurotransmitter to be identified, by Otto
Loewi. In the basal forebrain, clusters of cholinergic cells can be found
in the medial septal nucleus, the diagonal band of Broca, the nucleus
basalis of Meynert, and the substantia innominata. These cholinergic cells
project to the hippocampus and amygdala, amongst other sites. Cholinergic
neurons may be important in attention, learning and memory. Scopolamine
is a cholinergic antagonist, and it has deleterious effects on learning
and memory. (Rosenzweig et al., p. 83, 1999). People with Alzheimer's
disease have been showed to have low levels of ACh in the cerebral cortex
(Carter, 1998). ACh may also have role in the regulation of sleep.

Inhibiting acetylcholinesterase (AChE) causes decreased heart rate and blood
pressure. Many nerve gasses and insecticides target AChE, and death is typically
due to respiratory failure. This is because uninterrupted exposure to high
concentrations of ACh causes receptors to become desensitised.

Special enzymes
synthesise most of the neurotransmitters. The enzyme choline
acetylransferase (ChAT) causes a choline molecule to combine with the
enzyme acetyl coenzyme A (acetyl CoA) to produce a molecule of ACh.

Acetyl CoA is found in all cells. Choline is present in extracellular
fluid and it's uptake is the rate limiting step.

Acetyl CoA + choline
|
| ChAT
\|/
ACh + coenzyme A

The enzyme acetylcholinesterase (AChE) breaks down the ACh, leaving
choline and acetic acid.

(Rosenzweig et al., 1999, p. 84.)

2.4.1.2 Dopamine (DA)

"Dopamine controls arousal levels in many parts of the brain and is
vital for giving physical motivation. When levels are severly depleted -- as in
Parkinson's disease -- people may find it impossible to move forward
voluntarily. Low dopamine levels may also be implicated in mental stasis. Overly
high levels seem to be implicated in schizophrenia and
may give rise to hallucinations. Hallucinogenic drugs are thought to work on the
dopamine system." (Carter, 1998, p. 30.) Five subtypes of DA receptors have
been found, D1 an D5 are similar to each other, but different from D2, D3 and
D4. Haloperidol is a DA receptor antagonist, with a selectivity towards the D2
receptor, and is a potent antipsychotic. It is used to relieve the symptoms of
schizophrenia. (Rosenzweig et al., 1999, pp. 84-85.)

2.4.1.3 Norepinephrine (NE)

Neurons that release norepinephrine can be found in three main clusters in
the brain stem: the locus coeruleus complex in the pons, the lateral tegmental
system of the midbrain, and the dorsal medullary group. Norepinephrine
is also known as noradrenaline, and NE-producing cells are called noradrenergic.
(Rosenzweig et al., 1999, p. 85.) "[NE is] mainly an excitatory chemical
that induces physical and mental arousal and heightens mood. [The] locus
coeruleus [...] is one of several putative candidates for the brain's
'pleasure' centre." (Carter, 1998, p. 30.)

2.4.1.4 Serotonin (5-HT)

Most 5-HT cell bodies are found in the raphe nuclei. Humans have about
200,000 serotonergic cells (which is relatively little), but tracts and fibers
that release 5-HT extend throughout the brain. (Rosenzweig et al., 1999, p. 85.)
Serotonin is enhanced by Prozac, which modify some aspects of 5-HT activation.
High levels of 5-HT or high sensitivity to it are associated with serenity and
optimism, but it also affects other areas such as sleep, pain, appetite and
blood pressure (Carter, 1998, p. 30.)

2.4.1.5 Melatonin

2.4.1.6 Amino acids

The neurotransmitters glutamate and aspartate are excitatory, whereas gamma-aminobutyric
acid (GABA) and glycine are inhibitory. There are three large classes of GABA
receptors, called GABAA, GABAB, and
GABAC. GABAA receptors contain a
chloride channel, and are ionotropic. GABAB receptors are
coupled to G protein, they are metabotropic. GABAC, as A,
are ionotropic with a chloride channel, but they differ in subunit structure
from the other GABA receptors. Since the GABA recptors are inhibitory,
drugs that block the actions of GABA (GABA antagonists) are potent seizure
provokers. (Rosenzweig et al., 1999, p. 86.) GABA deficiency has been implicated
in anxiety states, epilepsy, and Huntingson disease.

Glutamate is the most abundant amino acid in the brain. It is the principle
mediator of synaptic execution in the CNS. Its causative role has been
demonstrated in the brain damage that results from cerebral anoxia (e.g.,
stroke, heart attack, siezures) and possibly epilepsy and some degenerative
brain diseases. There is also a glutamate theory
of schizophrenia. Glutamate binds with the ionotropic receptors AMPA, kainate, and NMDA. NMDA-type
glutamate receptors are active in a model of learning and memory. NMDA receptors
act differently from most other receptors because they are both ligand-gated and
voltage-gated.

The term "drug" is somewhat vague. Virtually all substances can
alter bodily effects. The term "drug" is reserved for those substances
that have pronounced effects when ingested in small quantities.

2.4.2.1 Ecstasy

3,4-methylendioxymetamphetamine (MDMA) is a derivative of amphetamine. MDMA
at low doses stimulates the release of dopamine. At
higher doses it also affect 5-HT activity. MDMA has been
shows to have neurotoxic effects: long-term loss of 5-HT neurons in non-human
primes. Less 5-HIAA in CSF of regular
users. Less 5-HT transporters, correlated with use. See dancesafe.org.

2.4.2.2 Hallucinogens

2.4.2.2.1 Lysergic acid diethylamide (LSD)

LSD's chemical structure is similar to serotonin. LSD
is a potent agonist of the 5-HT2A receptor (raphe
neurons). Presynaptic receptors: activating them causes a decrease in activity.
Similar changes occur during REM sleep. Hallucinogenic effects are NOT due to
this. Cortical areas are responsible for perception.

2.4.2.3 Cocaine

Blocks reuptake of both DA and NE. It has somewhat similar effects to those
of amphetamine. Tolerance does develop.

2.4.2.5 Nicotine

2.4.2.6 Opioids

The opioids are best known for their analgesic properties. They act on the CNS
to produce hypnotic effects and drowsiness, mood changes, and mental clouding.
Opioids act on the GI tract to produce decreased gastric motility and reduce
gastric and intestinal secretion, causing constipation. Autonomic effects
include diminished respiration and heart beat, and constricted pupils.

2.4.2.7 Alcohol (ethyl alcohol - ETOH)

ETOH has a biphasic action on the CNS; initial stimulant phase followed by a
more prolonged depressant phase. Low doses stimulate DA pathways. ETOH inhibits
the flow of Na+ ions across membranes, and it facilitates the GABAA
receptor making it more responsive. Remember that GABA is an inhibitory
neurotransmitter -- so when the receptor is more responsive, your motor actions
are (quite literally) inhibited.

2.4.2.8 Tranquillisers

2.4.2.9 Coffeine

Does not directly influence catecholamine systems. Coffeine is an antagonist
for the neuromodulator adenosine. Adenosine acts presynaptically to inhibit the
release of glutamate and dopamine. The net result is an increase in the release
of these neurotransmitters. Tolerance develops to the cardiovascular effects;
behavioural and psychological tolerance is weak.

2.4.3 Disease

2.4.3.1 Schizophrenia

Schizophrenia is a serious mental disorder that includes hallucinations,
delusions, and disruption of normal, logic thought processes.

2.4.3.1.1 Dopamine theory of schizophrenia

Drugs that block the activity of dopaminergic neurons alleviate the symptoms
of schizophrenia. It has been suggested that schizophrenia is produced by
overactivity of these neurons.

2.4.3.2 Parkinson's disease

Movement disorder that is characterised by a reduction in movement, poor
balance and resting tremor.

2.4.3.2.1 Dopamine theory of Parkinson's
disease

Parkinson's disease is due to the slow degeneration and eventual death of
dopaminergic neurons in the substantia nigra. It can be treated with L-dopa,
which leads to an increase of DA.